1. Field of the Invention
Small shallow painful mucosal ulcers of the mouth, commonly referred to as aphthous stomatitis, aphthous ulcers or canker sores in the medical literature, occur in about 25% of the general human population and are not contagious. They often appear on the unkeratinized oral mucosal surface of the soft palate, the ventral or lateral tongue, the buccal-labial mucosa, and the floor of the mouth, and usually recur at irregular intervals. They are often covered with a grayish white exudate and surrounded by a hyperemic or erythematous margin, and are highly sensitive, especially to acid food. The size of these ulcers is rarely more than 5 mm in diameter, but can be larger, and coalescence of multiple ulcers may occur. The pain caused by these ulcers may extend over the entire face. Small aphthous ulcers usually heal spontaneously in one to three weeks, but larger ulcers may require months to resolve, often with scarring.
Although aphthous ulcers were described by Hippocrates, the etiology of these lesions is still largely unknown. While a variety of conditions are associated with aphthous ulcers, immunologic status seems to be an important factor in initiating eruptions. For example, aphthous-like ulcers are often associated with allergic reactions, human immunodeficiency virus and herpes simplex infection. In some patients, the incidence of ulcer formation correlates with menstrual cycles. In other cases dietary or digestive disturbances seem to be the precipitating factors. Prolonged fever, emotional stress, local trauma, low serum iron, ferritin or zinc levels, deficiency of vitamin B.sub.12 or folate, malabsorption in association with celiac or Crohn's disease, food hypersensitivity and drug reactions may also promote aphthous ulcers.
The first stage of an emerging canker is a vesicle in the stratum granulosum of the mucosal squamous epithelium, produced by intraepithelial edema. The vesicle contains serum and degenerated epithelial cells, with little inflammatory response. This stage is rarely noticed, as the painful symptoms of the ulcer do not occur until the vesicle breaks, presenting an area of ulceration which disrupts the normal epithelium of the mucosa. Once an ulcer forms, the mucosa is no longer protected by an intact epithelium and the raw surface of the ulcer is exposed to microorganisms which normally inhabit the oral cavity.
Examples of indigenous oral flora include lactobacilli, actinomyces, leptotrichiae, .alpha.-hemolytic streptococci, enterococci, gram-positive cocci, Neisseriae, diphtheroid bacilli, fusiform bacilli, bacteroides, spirochetes, yeasts and Candida. When existent in normally balanced proportions, these microorganisms do not usually produce disease in the intact oral mucosa of a healthy person. However, upon rupture of a canker ulcer, opportunistic pathogens quickly destroy the remnants of the local surface barrier of the oral mucosa. The result is a secondary infection, characterized by a dense acute and a chronic inflammatory cell infiltration of the exposed connective tissue of the lamina propria mucosae at the crater of the ulcer. The necrotic tissue, fibrinous exudate and the inflammatory cells constitute a yellowish-white membrane often seen clinically covering the base of an ulcer.
Marked infiltration of the small neurovascular system occurs in the deeper layer of the lamina propria mucosae and at the periphery of the ulcer, which may account for the highly sensitive condition of the lesion and pain-inducing neuritis. The process of healing takes place only after the inflammation subsides, and is characterized by re-epithelialization of the ulcer, with or without scarring.
Despite the multifactorial etiology of aphthous ulcers, secondary infections arise after rupture of the intraepithelial vesicle during the early development of all cankers. Control of infection is essential for promoting the healing process. The diverse indigenous flora in the oral cavity possess a range of sensitivities to the chemotherapeutics of choice for the treatment of aphthous ulcers. During an ulcerative infection, stasis of key opportunistic pathogens can inhibit the growth of other dependent microbes, such that the group ceases to function as the causative agent for the infection.
An obstacle to inhibiting microbial proliferation is the fact that many bacteria are resistant to the concentrations of antibiotics attainable in blood or in tissues during medication. This property of drug resistance may be natural or acquired. However, the growth of many "resistant" microorganisms can be inhibited in vitro by increasing the concentrations of the antibiotic to a supratherapeutic level that is not safely attainable in blood or in tissue fluids via conventional gastrointestinal absorption or intramuscular and intravenous injections. For example, Gram-negative bacilli are generally regarded as being resistant to penicillin G, even at the concentration of 16 mcg/ml which is accepted as the average peak blood level after an intravenous injection of 500 mg of penicillin G. However, if a high concentration of penicillin G is used (such as, for instance, 740 mcg/ml) as the cut-off minimum inhibition concentration (MIC) for classifying sensitive and resistant strains, many Gram-negative bacilli (including, for instance, Salmonella, Shigella, most Escherichia coli strains, all Proteus mirabilis strains and most Bacteroides strains) would fall into the "sensitive" category. Needless to say, in clinical practice, drug toxicity and rapid renal clearance usually prevent this substantial level of antibiotic being achieved in human blood and tissue fluids via systemic oral or parenteral medication.
2. Description of Related Art
The treatment of aphthous stomatitis to date has been palliative, using various measures to lessen the pain, to control secondary infection, and to reduce inflammatory reaction after the painful ulcer is established. The treatments of choice for aphthous ulcers have varied over the years, but in general, palliative treatments have met with only limited success.
For example, in the 1950s, a recommended local treatment of infections of the oral cavity was lozenges of penicillin. The lozenges were prepared by compression of a mixture of amorphous penicillin or benzylpenicillin and dry granules of sucrose, lactose, or a mixture of the two, and suitable binding agents. Each lozenge weighed about 1 gram and contained not less than 90.0% of the prescribed or stated number of Units of penicillin, usually about 1000 Units (an equivalent of 0.625 mg of penicillin G) each. The lozenges were designed to disintegrate slowly, releasing penicillin over a period of 45 to 60 minutes, after which another lozenge was inserted, with this process continuing for 24 hours, except during meals. Adverse reactions included stomatitis upon treatment for more than two days, and a yellowish-brown to black discoloration of the tongue.
However, this topical treatment of aphthous ulcers with penicillin lozenges proved ineffective and was abandoned. Furthermore, as recently as 1980, the use of penicillin for topical applications to mucous membranes and skin was not advised, as such applications were described as ineffective and likely to produce hypersensitivity. (See "The Pharmacological Basis of Therapeutics", Eds. Gilman Goodman, and Gilman, p.1136.) As a result, this type of treatment for aphthous stomatitis was not included in later teachings.
Treatments for canker ulcers currently include a potent glucocorticoid ointment mixed with an equal volume of Orabase.TM. (active ingredient: mineral oil; available from Bristol-Myers Squibb of Canada), analgesics, topical anesthetics, such as viscous lidocaine hydrochloride, and various hygienic antiseptic mouth rinses. Systemic therapy with corticosteroids, colchicine, or dapsone in severe cases may be indicated. However, potent glucocorticoid ointments and systemic therapy with corticosteroids are known to be immunosuppressive, leaving patients vulnerable to complications, such as severe systemic bacterial or fungal infections. Thalidomide therapy for oral aphthous ulcers is effective in some HIV-infected patients, though the adverse effects of this teratogenic drug limit its usefulness in general. Topical treatment with tetracycline suspensions or nystatin suspensions, as well as systemic therapy with penicillin, are commonly employed. A drawback to oral antimicrobial rinses and suspensions is their inability to present high enough (supratherapeutic) concentrations of the active drugs in the immediate vicinity of the ulcers to suppress the growth of the pathogens which have contributed to and continue to perpetuate the infection. For example, one protocol requires patients to hold 250 mg of tetracycline in 5-10 mg/ml suspension in the mouth for 2 to 5 minutes to coat the ulcers, then suggests swallowing the remaining liquid. This treatment is often impractical, especially for use in children. Tetracycline oral suspensions are available commercially in concentrations from about 5 mg/ml to about 10 mg/ml. Supratherapeutic concentrations of, for example, 500 mg/ml are not achievable with these solutions. Likewise, topical combination treatments utilizing pastes of crushed tetracycline tablets (150 mg in 1 ml of saline) and tissue adhesive agents, such as cyanoacrylate, cannot achieve such high levels of antibiotic. Besides, this type of treatment must be performed by a dentist.
Some patients with recurrent aphthous stomatitis have responded to therapy with metal salts, such as zinc sulfate or the aluminum subsalt of sucrose-8-sulfate (sucralfate). Combinations of metal salts with antibiotics have proven effective for treating some forms of ulcers, such as gastrointestinal ulcers generated by, for example, Helicobacter pylori. Protective bioadhesive hydrogel patches made of cellulose have been used to abate oral ulcer pain and reduce healing time, but the patches alone do not address the infectious component of aphthous stomatitis. Therefore, these recommended treatments do not sufficiently meet the needs of many patients with aphthous ulcers.